Abstract 2022: Model-informed pediatric drug development: oral vinorelbine in low-grade glioma as a case study
Authors: Mourad HAMIMED, Pierre LEBLOND, Aurélie DUMONT, Florence GATTACCECA, Emmanuelle TRESCH-BRUNEEL, Alicia PROBST, Pascal CHASTAGNER, Anne PAGNIER, Emilie DE CARLI, Natacha ENTZ-WERLÉ, Jacques GRILL, Isabelle AERTS, Didier FRAPPAZ, Anne-Isabelle BERTOZZI-SALAMON, Caroline SOLAS, Nicolas ANDRÉ, Joseph Ciccolini
Journal: Cancer Research (2022)

Abstract Objectives:Defining a safe and effective dose in children is one of the biggest challenges in pediatric drug development. Pharmacometric tools are proposed as powerful quantitative techniques to leverage and integrate the collected data from pediatric clinical trials. Here we demonstrate and discuss the applications of nonlinear mixed effects (NLME) models through a detailed example of oral vinorelbine (VNR) in pediatric cancers.Methods:A multicentric, open-label, single-arm intervention phase II study was conducted. Patients with recurrent/progressive Low-Grade Glioma (LGG), were included. Patients received 60 mg/m² of oral VNR on days 1, 8 and 15 during the first 28-day treatment cycle and 80 mg/m² from cycle 2 to 12. Population pharmacokinetic (PK) analysis was performed using a NLME modeling approach on Monolix®. Fifty SNPs on PK-related genes were genotyped. The Influence of demographic, biological and pharmacogenetic covariates on VNR PK parameters was investigated using a stepwise multivariate procedure.Results:PK analysis included 36 patients with a median age (range) of 11 (6-17) years. A three-compartments model, with a delayed double zero-order absorption and a linear elimination, best described VNR pharmacokinetics. Typical population estimates (between-subject variability, between-occasion variability) for the apparent central volume of distribution (Vc/F) and elimination rate constant (k10) were 803 L (47%, 41%) and 0.60 h-1 (18%, 16%), respectively. Lower area under the concentration-time curve (AUC) levels were observed among children in comparison to adults. Following covariate analysis, BSA, leukocytes count, and ABCB1-rs2032582 SNP showed a dramatic impact on Vc/F. Additionally, ABCG2-rs2725264 A/G or G/G carriers and UGT2B7-rs7668258 T/T carriers showed higher k10 values. Conversely, age and sex had no significant effect on VNR PK.Conclusion:Higher doses may be necessary for children with LGG. A personalized dosing strategy, using BSA, leukocytes and ABCB1-rs2032582 SNP, could help to optimize the efficacy/toxicity balance of VNR in children. Model-informed drug development enabled efficiently a better understanding of PK of oral VNR in children and identifying several factors likely to explain the variability in VNR exposure and subsequent clinical outcomes. Citation Format: Mourad HAMIMED, Pierre LEBLOND, Aurélie DUMONT, Florence GATTACCECA, Emmanuelle TRESCH-BRUNEEL, Alicia PROBST, Pascal CHASTAGNER, Anne PAGNIER, Emilie DE CARLI, Natacha ENTZ-WERLÉ, Jacques GRILL, Isabelle AERTS, Didier FRAPPAZ, Anne-Isabelle BERTOZZI-SALAMON, Caroline SOLAS, Nicolas ANDRÉ, Joseph Ciccolini. Model-informed pediatric drug development: oral vinorelbine in low-grade glioma as a case study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2022.